After nearly 3 decades of concentrated research efforts, an effective HIV vaccine remains an elusive goal. Despite successes in generating vaccine induced T and B cell responses, there are no lead vaccine candidates currently in the pipeline. Evidence thus far suggests that both T and B cell responses will be required for broad-based population efficacy, both to prevent an initial localized tissue infection from becoming fully established and to modulate viremia should infection occur. To this end, it remains critical to define the effector arm of the HIV-specific CD8 T cell response, which is without question the one immune parameter that is most strongly associated with viral control. In addition, since vaccine studies will most effectively be performed in areas of high incidence of new infection, it will be critical to have comprehensive data regarding the circulating viral species in these populations, and the immune responses generated upon infection. Over the past funding period of this grant, we have made significant progress, working at the heart of the African epidemic, in establishing cohorts of persons with acute and chronic HIV infection, and using these to begin to define the immunogenicity, specificity, immunogenetics and function of the T cell response. Our data inidicate that ot all HIV-specific CD8 T cell responses contribute to control of viremia in vitro and in vivo. Moreover, in acute infection, during the most rapid decline in viremia, only a fraction of epitopes that become targeted in chronic infection are targeted, despite the presence of the cognate epitope in the infecting strain, and only a fraction of these appear to exert immune selection pressure. The goal of this competing renewal is to build on the firm foundation laid by progress during initial funding period of this grant to perform a comprehensive analysis of effective and ineffective immune responses against HIV during the critical period of acute infection, with the goal of defining those responses most important to induce with a protective vaccine, and those sequences most important to incorporate into an effective immunogen. Specifically, we propose to (1) determine the specificity and functional inhibitory capacity of HIV-1-specific CD8+ T cell responses in acute HIV-1 infection (2) Define the evolution of immune selection pressure applied in acute HIV-1 clade C virus infection by deep sequencing of subjects identified prior to seroconversion, and the impact on viral fitness and (3) Define the functional characteristics that define effective and ineffective CD8 T cell responses in acute clade C virus infection PUBLIC HEALTH RELEVANCE: With over 5 million new infections per year worldwide, the need for an effective vaccine has never been greater. With the first emergence of HIV-1-specific CD8+ T cells viral load decreases to a viral set point and this early viral set point has been associated with later disease outcome. We propose to investigate the relative selected contribution of the individual CD8+ T cell responses to the early viral set point and to understand the propensities of the effective versus ineffective CD8+ responses.